Impact of quantitative radiological features of interstitial lung disease on immunomodulatory treatment response in three autoimmune interstitial lung disease cohorts.

Background: The defining radiological features of autoimmune interstitial lung disease (ILD) are ground glass opacification (GGO) and fibrosis. The associations between these features and physiological response to immunomodulation remain unclear.

Methods: This study leveraged three autoimmune ILD cohorts: two with systemic sclerosis (SSc) and one with rheumatoid arthritis (RA) which were selected for inherent differences in fibrotic extents/patterns.

Biological correlates of radiological features of systemic sclerosis interstitial lung disease.

Background And Objectives: The extent and pattern of radiological features ( fibrosis and ground glass) can influence treatment approaches for systemic sclerosis-related interstitial lung disease (SSc-ILD). However, the pathobiology underlying these radiological features is poorly understood and warrants further investigation.

Methods: 68 proteins were measured in bronchoalveolar lavage (BAL) fluid from 103 SSc-ILD participants in Scleroderma Lung Study I.

Ventilation and features of the lung environment dynamically alter modeled intrapulmonary aerosol exposure from inhaled electronic cigarettes.

Electronic cigarettes (e-cigs) fundamentally differ from tobacco cigarettes in their generation of liquid-based aerosols. Investigating how e-cig aerosols behave when inhaled into the dynamic environment of the lung is important for understanding vaping-related exposure and toxicity. A ventilated artificial lung model was developed to replicate the ventilatory and environmental features of the human lung and study their impact on the characteristics of inhaled e-cig aerosols from simulated vaping scenarios.

Treatment Response Biomarkers for Systemic Sclerosis-Associated Interstitial Lung Disease.

Objective: This study investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) receiving treatment.

Methods: Participants of the Scleroderma Lung Study II, which compared receiving mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) for treating SSc-ILD, who had blood samples at baseline and 12 months were included. Levels for C-reactive protein (CRP), interleukin-6, C-X-C motif chemokine ligand (CXCL) 4, CCL18, and Krebs von den Lungen (KL)-6 were measured, and a logistic regression model evaluated relationships between changes in these biomarkers and the development of PPF by 24 months.

A Ventilated Three-Dimensional Artificial Lung System for Human Inhalation Exposure Studies.

Traditional in vitro and in vivo models for inhalation toxicology studies often fail to replicate the anatomical and physiological conditions of the human lung. This limitation hinders our understanding of intrapulmonary exposures and their related health effects. To address this gap, we developed a ventilated artificial lung system that replicates human inhalation exposures in four key aspects: (1) facilitating continuous breathing with adjustable respiratory parameters; (2) distributing inhaled aerosols through transitional airflow fields in 3D-printed airway structures, which enables size-dependent particle deposition; (3) duplicating the warm and humid lung environment to promote inhaled aerosol dynamics, such as hygroscopic growth; and (4) supporting the cultivation of human airway epithelium for aerosol exposure and toxicological analyses.

Sex differences in clinical outcomes and biological profiles in systemic sclerosis-associated interstitial lung disease: a post-hoc analysis of two randomised controlled trials.

Background: Observational studies have shown that men with systemic sclerosis have an increased risk of interstitial lung disease (ILD) and mortality compared with women. However, previous studies have not controlled for treatment effect or evaluated the biological mechanism or mechanisms underlying this sex difference. We aimed to compare ILD progression and long-term morbidity and mortality outcomes in male and female participants of two randomised controlled trials for systemic sclerosis-associated ILD.

Combining Clinical and Biological Data to Predict Progressive Pulmonary Fibrosis in Patients With Systemic Sclerosis Despite Immunomodulatory Therapy.

Objective: Progressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc-related interstitial lung disease (SSc-ILD).

Methods: Patients with SSc-ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC).

Association of Symptoms of Gastroesophageal Reflux, Esophageal Dilation, and Progression of Systemic Sclerosis-Related Interstitial Lung Disease.

Objective: To investigate whether symptoms of gastroesophageal reflux disease and radiographic measures of esophageal dilation are associated with radiographic progression of systemic sclerosis-related interstitial lung disease (SSc-ILD).

Methods: Participants of the Scleroderma Lung Study II, which compared mycophenolate versus cyclophosphamide for SSc-ILD, completed the reflux domain of the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 at baseline.

Hyaluronidase Enhances Targeting of Hydrogel-Encapsulated Anti-CTLA-4 to Tumor Draining Lymph Nodes and Improves Anti-Tumor Efficacy.

Immunotherapy targeting checkpoint inhibitors, such as CTLA-4 and/or PD-1, has emerged as a leading cancer therapy. While their combination produces superior efficacy compared to monotherapy, it also magnifies inflammatory and autoimmune toxicity that limits clinical utility. We previously reported that a peri-tumor injection of low-dose hydrogel-encapsulated anti-CTLA-4 produced anti-tumor responses that were equal to, or better than, systemic dosing despite a >80% reduction in total dose.

Blood Neutrophil Count and Neutrophil-to-Lymphocyte Ratio for Prediction of Disease Progression and Mortality in Two Independent Systemic Sclerosis Cohorts.

Objective: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc).

Methods: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity.

Peripheral blood gene expression profiling shows predictive significance for response to mycophenolate in systemic sclerosis-related interstitial lung disease.

Objectives: To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).

Methods: PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of composite modular scores for the course of forced vital capacity (FVC) per cent predicted measurements from 3 to 12 months.

Early Radiographic Progression of Scleroderma: Lung Disease Predicts Long-term Mortality.

Background: Radiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.

Research Question: Do short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?

Study Design And Methods: The Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively.

Systemic Sclerosis-Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration-Approved Therapies in Clinical Practice.

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases, and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the US Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-associated ILD (SSc-ILD): nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, 2 generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a phase II trial but are not FDA-approved for SSc-ILD.

Predictive Significance of Serum Interferon-Inducible Protein Score for Response to Treatment in Systemic Sclerosis-Related Interstitial Lung Disease.

Objective: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD.

Methods: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined.

Racial Disparities in Systemic Sclerosis: Short- and Long-Term Outcomes Among African American Participants of SLS I and II.

Objective: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II.

Methods: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF).

The MUC5B promoter variant does not predict progression of interstitial lung disease in systemic sclerosis.

Objective: To investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF).

Methods: SSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism.

Treatment With Mycophenolate and Cyclophosphamide Leads to Clinically Meaningful Improvements in Patient-Reported Outcomes in Scleroderma Lung Disease: Results of Scleroderma Lung Study II.

Objective: Our objective was to determine if treatment with cyclophosphamide (CYC) and mycophenolate mofetil (MMF) improves patient-reported outcomes (PROs) among patients with systemic sclerosis-related interstitial lung disease (SSc-ILD).

Methods: This study examined PROs in patients with SSc-ILD (N = 142) who participated in the Scleroderma Lung Study II, a randomized controlled trial comparing MMF for 2 years with oral CYC for 1 year followed by 1 year of a placebo. Joint models were created to evaluate the course of PROs over 2 years.

Peri-tumor administration of controlled release anti-CTLA-4 synergizes with systemic anti-PD-1 to induce systemic antitumor immunity while sparing autoimmune toxicity.

Combination immunotherapy targeting the PD-1 and CTLA-4 checkpoint inhibitor pathways provides substantial clinical benefit in patients with advanced-stage cancer but at the risk of dose-limiting inflammatory and autoimmune toxicity. The delicate balance that exists between unleashing tumor killing and promoting systemic autoimmune toxicity represents a major clinical challenge. We hypothesized that targeting anti-CTLA-4 so that it perfuses tumor-draining lymph nodes would provide a significant therapeutic advantage and developed an injectable hydrogel with controlled antibody release characteristics for this purpose.

Using Transitional Changes on High-Resolution Computed Tomography to Monitor the Impact of Cyclophosphamide or Mycophenolate Mofetil on Systemic Sclerosis-Related Interstitial Lung Disease.

Objective: To examine changes in the extent of specific patterns of interstitial lung disease (ILD) as they transition from one pattern to another in response to immunosuppressive therapy in systemic sclerosis-related ILD (SSc-ILD).

Methods: We evaluated changes in the quantitative extent of specific lung patterns of ILD using volumetric high-resolution computed tomography (HRCT) scans obtained at baseline and after 2 years of therapy in patients treated with either cyclophosphamide (CYC) for 1 year or mycophenolate mofetil (MMF) for 2 years in Scleroderma Lung Study II. ILD patterns included lung fibrosis, ground glass, honeycombing, and normal lung.

Pulmonary effects of inhaled cannabis smoke.

The smoke generated from cannabis delivers biologically active cannabinoids and a number of combustion-derived toxins, both of which raise questions regarding the impact of cannabis smoking on lung function, airway inflammation and smoking-related lung disease. Review the potential effects of cannabis smoking on respiratory symptoms, lung function, histologic/molecular alterations in the bronchial mucosa, smoking-related changes in alveolar macrophage function and the potential clinical impact of cannabis smoking on chronic obstructive pulmonary disease, lung cancer and pulmonary infections. Focused literature review.

Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18.

Objective: To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).

Methods: Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels.

Cyclophosphamide for Systemic Sclerosis-related Interstitial Lung Disease: A Comparison of Scleroderma Lung Study I and II.

Objective: To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II.

Methods: Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2).

Minimal Clinically Important Differences for the Modified Rodnan Skin Score: Results from the Scleroderma Lung Studies (SLS-I and SLS-II).

Objective: This study aimed to assess the minimal clinically important differences (MCIDs) for the modified Rodnan skin score (mRSS) using combined data from the Scleroderma Lung Studies (I and II).

Methods: MCID estimates for the mRSS at 12 months were calculated using three anchors: change in scores on the Health Assessment Questionnaire- Disability Index from baseline to 12 months, change in scores on the Patient Global Assessment from baseline to 12 months, and answer at 12 month for the Short Form-36 health transition question "Compared to one year ago, how would you rate your health in general now?" We determined the mRSS MCID estimates for all participants and for those with diffuse cutaneous systemic sclerosis (dcSSc). We then assessed associations between MCID estimates of mRSS improvement and patient-reported outcomes, using Student's t test to compare the mean differences in patient outcomes between those who met the MCID improvement criteria versus those who did not meet the improvement criteria.